Detection and Pharmacokinetics of Etoricoxib in Thoroughbred Horses

Etoricoxib, a selective inhibitor of cyclooxygenase-2, is used in the treatment of many inflammatory diseases and dental pain in humans. The aim of this study was to determine the pharmacokinetics and metabolism of etoricoxib in horses. Six horses weighing an average of 475 ± 25 kg were administered a single oral dose of etoricoxib at 1 mg/kg body weight. The results show that the drug reached a maximum concentration of 505.2 ± 67.8 ng/mL in 48 minutes after administration. The elimination half-life was calculated to be 10.20 ± 1.30 hours. Mass spectrometric analysis confirmed that etoricoxib is metabolized in horses via the oxidation of its 6′-methyl group to form a hydroxyl methyl etoricoxib which can further be oxidized to form either an acid or be glucuronidated. In addition, the 1′-N terminal of 6′-hydroxymethyl metabolite is oxidized to form the corresponding 1′-N oxide metabolite. The present results have clearly demonstrated that etoricoxib is mainly excreted in urine as metabolites. From these data, it is also possible to postulate a detection time for the metabolites which in turn can assist in the control of illegal use of the drug in horse racing.     

恩诺沙星及其代谢产物在中华绒螯蟹血淋巴中的比较药代动力学

研究了不同水温(16℃、25℃)、不同给药剂量(10 mg/kg、20 mg/kg)和不同给药方式(肌注、口灌)等条件下,恩诺沙星及其代谢产物环丙沙星在中华绒螯蟹体内的药代动力学,比较了不同条件下药物在蟹血淋巴中的吸收、分布和代谢的差异。结果表明,恩诺沙星在蟹血淋巴中的药-时数据符合开放式二室模型。16℃时以10 mg/kg剂量肌注给药后,恩诺沙星在蟹血淋巴的主要药代动力学参数为:AUC96.818 mg/(L.h),Cmax6.54μg/mL,t1/2α0.851 h,t1/2β95.415 h;25℃时以10 mg/kg剂量肌注给药后,恩诺沙星的主要药代动力学参数为:AUC168.457 mg/(L.h),Cmax7.12μg/mL,t1/2α0.58h,t1/2β88.833 h;25℃时以20 mg/kg剂量肌注给药后,恩诺沙星的主要药代动力学参数为:AUC155.612 mg/(L.h),Cmax11.045μg/mL,t1/2α5.239h,t1/2β88.378 h;25℃时以10 mg/kg剂量口灌给药后,恩诺沙星的主要药代动力学参数为:AUC86.525 mg/(L.h),Cmax3.469μg/mL,t1/2α8.071h,t1/2β61.842 h。不同条件下,恩诺沙星在蟹血淋巴中的主要药代动力学参数差异较大。恩诺沙星的活性代谢产物环丙沙星在各种给药条件下的蟹血淋巴中均能检出,但含量均处于较低值,且药-时数据不能用房室模型拟合,表明恩诺沙星在蟹体内只有极少部分代谢为环丙沙星。     

Disodium-fosfomycin pharmacokinetics and bioavailability in post weaning piglets

Disodium-fosfomycin pharmacokinetics has been studied in different species after oral, intravenous, intramuscular and subcutaneous administration. At present there are neither documented clinical experiences of the use of fosfomycin in pigs nor any published studies in weaning piglets, although it is a period of high incidence of infectious diseases. The pharmacokinetics and the bioavailability of sodium fosfomycin were studied in post weaning piglets after intravenous and intramuscular administration of 15 mg/kg of body weight. Plasma concentrations were measured by a high-performance liquid ms/ms. After IV administration the area under the fosfomycin concentration:time curve in plasma was AUC_(0–12) of 120.00 ± 23.12 μg h/ml and the volume of distribution (Vd) of 273.00 ± 40.70 ml/kg. The elimination was rapid with a plasma clearance of 131.50 ± 30.07 ml/kg/h and a T_1/2 of 1.54 ± 0.40 h. Peak serum concentration (C_max), T_max, AUC_(0–12) and bioavailability for the IM administration were 43.00 ± 4.10 μg/ml, 0.75 ± 0.00 h, 99.00 ± 0.70 μg h/ml and 85.5 ± 9.90% respectively. Different authors have determined a minimum inhibitory concentration (MIC₉₀) ranging from 0.25 μg/ml for Streptococcus sp. and 0.5 μg/ml for Escherichia coli. Considering the above, and according to the values of plasma concentration vs time profiles observed in this study, effective plasma concentrations of fosfomycin for sensitive bacteria can be obtained following IV and IM administration of 15 mg/kg in piglets.     

Permeability determination and pharmacokinetic study of nobiletin in rat plasma and brain by validated high-performance liquid chromatography method

In the present study, we are reporting permeability and pharmacokinetics of nobiletin in rat plasma and brain, using a validated reverse phase high performance liquid chromatographic method. Protein precipitation method was used for the extraction of nobiletin and coumarin (IS) from rat plasma and brain tissue. The system was run in isocratic mode with mobile phase consisting of potassium dihydrogen ortho-phosphate (pH 4.5; 0.04 mM) and acetonitrile in ratio of 50:50, v/v. The total chromatographic run time was 9.0 min. The method was proved to be accurate and precise at linearity range of 0.05–10 μg/mL with a correlation coefficient (r) of ≥ 0.994 in rat plasma and ≥ 0.995 in rat brain. The intra- and inter-day precision and accuracy values are found to be within the assay variability limits as per the FDA guidelines. Nobiletin was found stable in the battery of stability studies viz., bench-top, auto-sampler, freeze/thaw cycles and long term storage in a freezer at − 70 ± 10 °C. Maximum concentrations of nobiletin in both plasma and brain were observed at 1 h after single oral dosing (50 mg/kg). The maximum concentration in plasma and brain were 1.78 and 4.20 μg/mL, respectively. The AUC_0–t in plasma and brain were 7.49 and 20.66 μg·h/mL, respectively. The mean elimination half life (t_1/2) in plasma and brain were 1.80 and 11.42 h, respectively. The Parallel Artificial Membrane Permeability Assay (PAMPA) permeability of nobiletin was found to be high at both pH 4.0 and 7.0.     

An in vivo analysis of the therapeutic and synergistic properties of Chinese medicinal formula Yin-Chen-Hao-Tang based on its active constituents

6,7-Dimethylesculetin (D), geniposide (G) and rhein (R) are the three major active ingredients of Yin-Chen-Hao-Tang (YCHT), a famous Chinese herbal formula, which has been shown to be clinically effective for treating hepatic injury (HI) syndrome. The present study was conducted to investigate the therapeutic and synergistic effects of COC (combination of D, G and R) on HI rats by combining pharmacokinetic with biochemical analysis strategy. Plasma was analyzed by using reversed-phase high performance liquid chromatography (RP-HPLC). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models were built to evaluate the therapeutic and synergistic effects of COC at the biochemical level. Here, we report that the COC combination could increase the plasma level, slow elimination rate, exert a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of HI. Overall, this beneficially accounts for the popular view that traditional Chinese medicine (TCM) formula usually takes multi-component to exert their therapeutic effects. We suggest that dissecting the mode of action of clinically effective formula to be capable of producing a sufficient effect at low doses.     

甲砜霉素在鲤鱼中的药代动力学研究

本实验在(26±2)℃的养殖水温下,采用高效液相色谱–串联质谱法(HPLC-MS/MS)研究了以30 mg/(kg·bw)的剂量对鲤鱼(Cyprinus carpio)进行单次投喂药饵后甲砜霉素(Thiamphenicol,TAP)在鲤鱼体内的药物代谢动力学。通过DAS 2.0动力学软件分析TAP在鲤鱼体内的药–时数据,结果表明符合一级吸收二室模型。TAP在肌肉、肾脏、肝脏、鱼皮、鳃、脾脏和血浆各组织的药物达峰时间(T_(peak))分别为16、2、16、8、0、2和16 h,达峰浓度(C_(max))分别为15.6、35.3、12.4、9.0、33.0、11.6 mg/kg和21.0 mg/L;药–时曲线下面积(AUC)分别为1084.5、1578.1、777.3、541.1、0.1、478.1 mg/(kg·h)和485.1 mg/(L·h),消除半衰期(t_(1/2β))分别为11.4、100.2、54.2、41.1、69.5、38.0和71.9 h。TAP在鲤鱼体内各组织的分布和消除速率相差较大;在肾脏中的药物达峰时间短且达峰浓度高于其他组织,其消除半衰期也明显高于其他组织,推测肾脏是鲤鱼体内TAP蓄积和代谢的主要器官。按照农业部《动物性食品中兽药最高残留限量》文件规定,TAP在水产动物中最高残留限量(MRL)不得高于50μg/kg,本研究中,肌肉、肾脏、肝脏、鱼皮、脾脏和血浆的TAP残留量低于MRL的时间分别从第16、16、12、12、12、10和12天开始,将肌肉和肾脏作为TAP药物残留的靶组织,建议休药期不得低于16 d。     

植物雌激素大豆苷元的药物动力学研究进展

植物雌激素大豆苷元具有抗氧化活性、心血管保护作用、抗癌作用、消炎作用、抗溃疡作用及雌激素等多种药理功能。综述大豆苷元的药物动力学方面的研究进展,为大豆苷元的药剂学研究和发展以大豆苷元为先导物的前药修饰提供科学依据。     

敌百虫在乌鳢体内和水环境中的代谢动力学及残留研究

[目的]明确敌百虫在水产养殖中的安全性。[方法]全池泼洒0.5 mg/L敌百虫,采用气相色谱法测定敌百虫在乌鳢体内的代谢动力学和残留消除规律。[结果]乌鳢组织和水样中敌百虫的最低检测限为0.02μg/m L。随着时间的延长,敌百虫在乌鳢血液中的浓度逐渐升高,120 h达最高,为0.072 mg/kg,至360 h时未检出。肌肉中12 h内未检出,24 h浓度为0.023 mg/kg,120 h检出最大浓度0.051 mg/kg,至288 h未检出。肝脏8 h未检出,12 h检出浓度为0.026 mg/kg。使用敌百虫后,乌鳢体内的药物残留量均低于我国的兽药最高残留限量要求,但在养殖水体中的残留时间较长,降解半衰期为35.19 h。[结论]为确保敌百虫使用后对水生态环境及食品安全,建议敌百虫使用后的休药期为150℃·d。     

3种磺胺类药物在中国对虾(Fenneropenaeus chinensis)体内的药代动力学特征

采用高效液相色谱法研究了3种磺胺类药物在中国对虾体内的药物代谢动力学特征,这3种磺胺类药物包括磺胺二甲嘧啶(SM2)、磺胺嘧啶(SD)及磺胺对甲氧嘧啶(SMD)。实验期间,中国对虾的养殖水温为(24.6±2.4)℃,单次口服3种磺胺类药物的剂量均为100 mg/kg。结果显示,3种磺胺类药物在中国对虾体内的血药经时过程均符合一级吸收二室开放模型,SM2的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为25.812 h、34.066 mg/L·h、94.553 L/kg、2.608 L/h·kg、2 h、1.07 mg/L;SD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为46.446 h、45.39 mg/L·h、97.207 L/kg、1.504 L/h·kg、1 h、1.17 mg/L;SMD的主要药动学参数T1/2β、AUC、Vd、CL、Tmax、Cmax分别为66.296 h、65.917 mg/L·h、40.015 L/kg、0.763 L/h·kg、2 h、2.00 mg/L。结果表明,SMD在中国对虾体内分布比SM2、SD更广泛;中国对虾体内SM2的消除相半衰期最短,SD次之,SMD消除相半衰期最长;3种磺胺类药物在中国对虾体内72 h药物吸收量SMD最高,SD次之,SM2最低;且SMD药物清除率最低,SD次之,SM2药物清除率最高,所以口服3种磺胺类药物72 h中国对虾体内SMD残留最多,SD次之,SM2残留最少。SMD在中国对虾体内药效更加持久,故在不考虑使用成本及毒副作用等其他因素的前提下,比较这3种磺胺类药物的药物代谢动力学特征,更加推荐使用SMD。     

恩诺沙星及其代谢产物环丙沙星在牙鲆体内代谢消除规律

以80 mg/kg鱼体重对牙鲆单次口灌给药恩诺沙星,给药后在不同的时间点取样,用高效液相色谱荧光检测器检测,研究恩诺沙星及其主要代谢产物环丙沙星在牙鲆体内的代谢消除规律。研究表明,停药后0.25 h,肌肉中恩诺沙星残留量最低。各组织的消除半衰期依次为腮肝脏血液肾脏肌肉,其中肌肉中恩诺沙星消除半衰期最低为67.759 h,消除最快,停药后12 d检测不到恩诺沙星。停药后0.25 h,在牙鲆血液、肝脏、肾脏中均有环丙沙星残留,残留量依次为肝脏肾脏血液,肌肉和鳃中未检出环丙沙星。停药后22 d在血液、肝脏和肾脏3个组织中仍然能够检测出恩诺沙星,但是停药7 d后这3个组织中均检测不出环丙沙星。结果显示,恩诺沙星在牙鲆体内代谢速度较慢,而且只是在一段时间内有脱乙基代谢为环丙沙星的反应发生,但并不是在恩诺沙星消除的全过程都发生,而且代谢物环丙沙星在牙鲆体内的消除速度要比恩诺沙星快。